This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aims of this proposal have not changed. They are designed to address the hypothesis that under hyperglycemic conditions, increased metabolism of glucose by aldose reductase (AR) exacerbates hypercholesterolemia-induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and thereby promotes macrophage activation and atherogenesis. It has been established that accumulation of excessive cholesterol in macrophage-derived foam cells leads to ER stress and activates UPR. This pathway has recently emerged as a unifying theme in atherosclerosis and diabetes research and UPR has been suggested to be the major cause of insulin resistance. Despite these advances, the mechanisms leading to the activation of ER stress and specific consequences of its activation for macrophage proinflammatory response and foam cell formation is not known. Specifically, we proposed: 1. Examine whether high glucose increases foam cell formation, cytokine production and apoptosis in cholesterol-loaded macrophages. 2. Determine whether high glucose modulates cholesterol-induced macrophage activation by triggering UPR. 3. Delineate the contribution of UPR activation to cytokine production and atherosclerotic lesion formation in diabetic mice.